Various Ageing Stubs

Autophagy

Autophagy is the process by which cells (or cellular components) eat themselves under conditions of nutrient deprivation (AKA fasting)

https://podcastnotes.org/2019/07/11/autophagy/

Alzheimer’s

The vaccine research involved a new field in immunology called endobody vaccines.

Endobodies: Most vaccines prepare our body’s immune system to fight off so-called exogenous disease, such as measles or flu, caused by bacteria or viruses entering our blood. Endobody vaccines, on the other hand, prime our immune system to deal with malfunctioning internal parts of the body that it would otherwise ignore.

United Neuroscience.

(earlier work) epitopes – fragments of proteins, five to six amino acids long, that play a critical role in the body’s defence against external diseases.
The human immune system relies on a collection of cells and proteins to identify, neutralise and destroy invaders. The body’s first two lines of defence are inflammation and the so-called neutrophil cells. Inflammation is caused by damaged cells releasing chemicals that cause blood vessels in the area to leak, swelling the tissue with fluid and isolating the foreign substance. Neutrophils are white blood cells that then ingest invaders and break down their protein chains. The next wave of defence – white cells called microphages – “eat” the neutrophils, extracting fractions of the invading proteins and attaching them to the surface of their cell wall. These fractions are the so-called epitopes.

After the body has defeated the invasion, it stores a blueprint of the successful B cells and T cells. This makes it much faster at fighting another bout of the same disease, swamping the threat before it has time to spread. Most immunisation against disease involves mimicking an infection by injecting an inactivated or attenuated form of the invader to trigger the immune system – should an infection occur, the immune system will then respond before the person becomes ill.

She created synthetic versions of the tiny chains of amino acids that trigger the production of antibodies. In the case of her Alzheimer’s vaccine, this allowed her to develop a mechanism that triggers antibodies to the Alzheimer’s protein in the blood. These then attract T cells that attack any protein with an antibody attached.

Chang Yi’s vaccines use molecules that are so small, they don’t trigger inflammation.

Since then the disease has risen to become the leading cause of death for women and the second leading cause for men in the UK: combating Alzheimer’s would be a dramatic medical achievement. 

Over the last 15 years, UK mortality statistics have shown a steady decline in deaths from heart disease, strokes and most major cancers – for men and women. Over the same period the death rate from dementia – of which Alzheimer’s is the most common cause – has doubled: in part because lifespans have increased, and the effects of the disease increase with age. In the UK, there are currently 850,000 people living with dementia, and 500,000 – perhaps as many as two-thirds – have Alzheimer’s. 

A total of five drugs are available to relieve symptoms, but they cannot slow or stop the progression of the disease. There is no known cure. Following diagnosis, life expectancy is typically between three and nine years.

Although we don’t know much about Alzheimer’s, researchers believe its effects are caused by two rogue proteins, beta-amyloid and tau – high amounts of both are found in the brains of people with Alzheimer’s. Beta-amyloid was discovered in 1984, with tau identified two years later.

For reasons that are unclear, damaged beta-amyloid can misfold into a “sticky” form that clumps together in a tangle of fibres – called plaques – that accumulate around nerve cells and disrupt cell communication, metabolism and repair. 

Both proteins may cause brain cell damage, although researchers aren’t sure if high levels of beta-amyloid and tau cause Alzheimer’s or are symptoms of the condition. 

Chang Yi’s vaccine – UB-311 ( UB-312, the Parkinson’s vaccine )– couples a synthetic imitation of a common disease with a specific sequence of amino acids that are present only in the damaged beta-amyloid protein, and absent in the healthy form. This provokes an antibody response, clearing the tangled proteins away without provoking potentially damaging inflammation.

In January 2019, the company announced the first results from a phase IIa clinical trial in 42 human patients. “We were able to generate some antibodies in all patients, which is unusual for vaccines,” Chang Yi explains with a huge grin. “We’re talking about almost a 100 per cent response rate. So far, we have seen an improvement in three out of three measurements of cognitive performance for patients with mild Alzheimer’s disease.”

to immuno-sculpt people against chronic illness and chronic ageing with vaccines as prolific as vaccines for infectious diseases.

https://www.wired.co.uk/article/alzheimers-vaccine-united-neuroscience

Links June-July 2019

June-July 2019 – not all links, will be more consistent in the future.

https://link.springer.com/referenceworkentry/10.1007%2F978-3-319-69892-2_395-1

Big library, found originally via Longevity Activism post/page on there

https://www.sciencedaily.com/releases/2019/06/190617164701.htm

Antioxidant puts up fight, but loses battle against protein linked to Alzheimer’s disease

http://arep.med.harvard.edu/gmc/protect.html

Genetic alleles and protection they offer

https://www.ldeming.com/longevityfaq#explanation

Good beginners post, Laura Deming

https://onlinelibrary.wiley.com/doi/full/10.1111/j.1474-9726.2009.00533.x

Mouse studies, only 1/5 (at least in this paper) showed longer lives through caloric restriction, some shorter

https://podcastnotes.org/2019/01/30/sinclair/

Interview with David Sinclair, notes from the podcast with many interesting links

https://podcastnotes.org/2019/01/17/attia-5/

Interview with Peter Attia, notes from the podcast with many interesting links

https://podcastnotes.org/2018/08/14/mtor/

Interview with David Sabatini, notes from the podcast with many interesting links, mtor discussion, Rapamycin

https://podcastnotes.org/2019/07/11/autophagy/

Podcast, Mike Mutzle, autophagy

https://www.nytimes.com/2019/07/15/opinion/future-billionaires.html

Paul Krugman, NYT, billionaires shouldn’t live forever, opinion piece (imagined future)

https://www.youtube.com/watch?v=Yfd041nvaIo&t=0s

Engineering Better Medicines from our Own Cells | Krystyn Van Vliet | TEDxMIT – better way to grow cells (outside the body) and use them as therapies

https://singularityhub.com/2019/07/30/scientists-just-released-a-new-playbook-for-engineering-longer-healthier-lives/

Playbook, described in Singularity Blog

Resveratrol

Promoted by David Sinclair, has financial stake, NAD boosters

” What is theoretically possible in the future remains unproven in humans and not ready for sale, experts say. “

Research by Sinclair and others helped spark interest in resveratrol, an ingredient in red wine, for its potential anti-aging properties. 

Sinclair co-founded a company, Sirtris, to test resveratrol’s potential benefits and declared in an interview with the journal Science it was “as close to a miraculous molecule as you can find.” GlaxoSmithKline bought the company in 2008 for $720 million. By the time Glaxo halted the research in 2010 because of underwhelming results with possible side effects, Sinclair had already received $8 million from the sale, according to Securities and Exchange Commission documents. He also had earned $297,000 a year in consulting fees from the company, according to The Wall Street Journal. (ok… XD)

“If you want to make money, hiring a sales rep to push something that hasn’t been tested is a really great strategy,” said Miller, who is testing substances on mice. “If instead you want to find drugs that work in people, you take a very different approach. It doesn’t involve sales pitches. It involves the long, laborious, slogging process of actually doing research.”

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Top cited papers on google scholar:

Cancer chemopreventive activity of resveratrol, a natural product derived from grapes [1] 5,456 citations, Jang et al., 1997

mostly in mice / cultures

meta-study

most in mice, good effects

Resveratrol, a phytoalexin found in grapes and other food products, was purified and shown to have cancer chemopreventive activity in assays representing three major stages of carcinogenesis. Resveratrol was found to act as an antioxidant and antimutagen and to induce phase II drug-metabolizing enzymes (anti-initiation activity); it mediated anti-inflammatory effects and inhibited cyclooxygenase and hydroperoxidase functions (antipromotion activity); and it induced human promyelocytic leukemia cell differentiation (antiprogression activity). In addition, it inhibited the development of preneoplastic lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. These data suggest that resveratrol, a common constituent of the human diet, merits investigation as a potential cancer chemopreventive agent in humans.

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Biological effects of resveratrol [2] 1741 citations

Full article not available, seems to be summary of research

” However, the bioavailability and metabolic pathways must be known before drawing any conclusions on the benefits of dietary resveratrol to health. “

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Therapeutic potential of resveratrol: the in vivo evidence [3], 3315 citations, 2006

By Joseph A. Baur, and David A. Sinclair.

Resveratrol, a constituent of red wine, has long been suspected to have cardioprotective effects. Interest in this compound has been renewed in recent years, first from its identification as a chemopreventive agent for skin cancer, and subsequently from reports that it activates sirtuin deacetylases and extends the lifespans of lower organisms. Despite scepticism concerning its bioavailability, a growing body of in vivo evidence indicates that resveratrol has protective effects in rodent models of stress and disease. Here, we provide a comprehensive and critical review of the in vivo data on resveratrol, and consider its potential as a therapeutic for humans

Review of literature

Resveratrol has been considered to be a caloric restriction mimetic in lower organisms, primarily on the basis of its activation of sirtuin proteins and its capacity to extend lifespan9,14. In mammals, caloric restriction and resveratrol treatment afford protection against a similar spectrum of diseases (TABLE 1), justifying further investigation into the potential overlap in mechanism of action.

It is fair to say that the literature on resveratrol is, in many cases, contradictory and confusing. The wide range of concentrations and doses used to achieve the various effects reported for resveratrol (~32 nM–100 µM in vitro and ~100 ng–1,500 mg per kg (body weight) in animals) raises many questions about the concentrations that are achieved or achievable in vivo. Furthermore, resveratrol has a short initial half-life (~8–14 min for the primary molecule175,176) and is metabolized extensively in the body. As such, calculating the effective in vivo concentration of resveratrol or designing new studies based on the current literature can be daunting

In mammals, there is growing evidence that resveratrol can prevent or delay the onset of cancer, heart disease, ischaemic and chemically induced injuries, diabetes, pathological inflammation and viral infection. These effects are observed despite extremely low bioavailability and rapid clearance from the circulation. Administering higher doses to improve efficacy might not be possible as toxic effects have been observed at or above 1 g per kg (body weight)147. Moreover, administering a daily dose to a human weighing 75 kg with 100 mg per kg (body weight) of resveratrol would require 2.7 kg of resveratrol a year, at a current cost of about US$6,800. Therefore, blocking the metabolism of resveratrol, developing analogues with improved bioavailability, or finding new, more potent compounds that mimic its effects will become increasingly important.

However, activation of the mammalian Sir2 homologue SIRT1 by resveratrol has yet to be demonstrated in vivo, and our current lack of understanding of how caloric restriction brings about its effects precludes a more definitive mechanistic comparison

See references at the end for some good footnotes!

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What about recent papers?

Mwah, nothing really good in humans…

https://khn.org/news/a-fountain-of-youth-pill-sure-if-youre-a-mouse/

Prof. dr. J.H.J. Jan Hoeijmakers

Jan Hendrik Jozef Hoeijmakers (Sevenum, 15 March 1951) is a Dutch molecular biologist, biochemist and molecular geneticist. He is known for his clarification of the DNA repair mechanisms and the effects of defects in the repair mechanism on genetic stability in old age, cancer and various hereditary disorders.

https://nl.wikipedia.org/wiki/Jan_Hoeijmakers

The team of Jan Hoeijmakers succeeded in cloning the first human DNA repair gene, Ercc1, followed by many more, discovered the very strong evolutionary conservation of DNA repair and an unexpected link with basal transcription.

His team identified which repair processes primarily protect from cancer and which from accelerated aging and succeeded in getting grip on the aging process in mice by modulating DNA repair and surprisingly by nutritional interventions. 

Rapid accumulation of unrepaired DNA damage in these mice may cause cancer or premature cell death and senescence, but triggers also an anti-aging, anti-cancer ‘survival response’ likely in an attempt to extend lifespan. 

In 2005 Hoeijmakers started a company called DNage and in 2012 he founded AgenD whose mission is to provide solutions for medical/health problems associated with aging. 

https://www.oncode.nl/research/groups/jan-hoeijmakers-group

Jan Hoeijmakers is Prof. Molecular Genetics at the Erasmus Medical Center in Rotterdam, the Netherlands. His research focuses on the mechanism and clinical impact of mammalian DNA repair. His team cloned half of the genes involved in nucleotide excision and transcription-coupled repair, enabling elucidation of the underlying molecular mechanisms, and generated the largest set of mouse repair mutants allowing insight into the etiology of human repair syndromes. He discovered that DNA damage and consequent transcription stress is a main cause of ageing and that dietary restriction dramatically delays accelerated aging in mouse repair mutants and corresponding human patients by reducing DNA damage. These findings have wide clinical implications for many aging-related diseases most strongly neurodegeneration, for reducing side effects of chemo- and radiotherapy, and ischemia reperfusion injury associated with surgery and organ transplantation. Jan Hoeijmakers heads research teams in the Erasmus Medical Center, the Princess Máxima Center for Pediatric Oncology in Utrecht and the CECAD in Cologne. For his scientific achievements Hoeijmakers has obtained many (inter)national awards and distinctions including the Spinoza award, Louis Jeantet Prize for Medicine in Europe, the Josephine Nefkens Prize for cancer research, 2 subsequent ERC advanced grants, the Koningin Wilhelmina Research Prize of the Dutch Cancer Society, recently the Thon Award of the Olav Thon Stiftelsen, etc.

https://ssiem2019.org/prof-dr-j-h-j-jan-hoeijmakers/

Articles

https://scholar.google.nl/scholar?hl=en&as_sdt=0%2C5&q=J.+H.+J.+Hoeijmakers&btnG=

Web archive, erasmus MC profile

https://web.archive.org/web/20170201220024/http://www.erasmusmc.nl/MScMM/faculty/CVs/hoeijmakers_cv?lang=en

Rapamycin

DEF

Article: Rapamycin directly activates lysosomal mucolipin TRP channels independent of mTOR

https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000252

https://news.umich.edu/a-new-pathway-for-an-anti-aging-drug/

Rap and rapalogs promote autophagy via a TRPML1-dependent mechanism. Given the demonstrated roles of TRPML1 and TFEB in cellular clearance, we propose that lysosomal TRPML1 may contribute a significant portion to the in vivo neuroprotective and anti-aging effects of Rap via an augmentation of autophagy and lysosomal biogenesis.

  • “If you look at the administration of rapamycin across about a billion years worth of evolutionary animal models, everything from yeast to worms, fruit flies to mammals (mice and dogs), this compound seems to universally increase life”
  • Rapamycin binds to a complex, called mTOR (mechanistic target of rapamycin) in our cells and inhibits its function
  • mTOR regulates autophagy
    • When mTOR activity is turned down (by taking rapamycin), the body is more likely to undergo autophagy
      • Autophagy is the process by which cells eat themselves – the dysfunctional cells (like cancer cells) tend to be “eaten” first
    • In a sense – the inhibition of mTOR mimics what happens to the body in a nutrient sparse environment
  • Peter has been taking 5 mg of rapamycin for the last 3 months (he doesn’t specify how often, but it sounds like every 4-7 days)

  • In the Mannick study, the negative side effects when taking 5 mg of rapamycin once per week, compared to taking 1 mg every day, didn’t seem to be that much worse
    • But taking 20 mg once per week vs. 5 mg once per week, showed no additional immune benefit (however there were more negative side effects)
  • Matt Kaeberlein has done some studies on dogs, suggesting the optimal dosing in humans would be around 4-8 mg, in some sort of pulsatile/episodic fashion (every other day or every third day)
    • Why? – You don’t want to inhibit MTORC2 
      • If you dose with rapamycin every day, you don’t allow for TOR to be recirculated, and within a few days of consecutive dosing, you start to inhibit the creation of mTORC2
  • So in short, there’s no side effects to taking too little (just a lack of benefit), but you want to be careful about taking too much
  • If Peter were to guess the perfect dose: 4-6 mg every 4-7 days

  • Rapamycin (a drug) acts on a protein called mTOR (it inhibits its function)
  • Insulin, glucose, and amino acids activate mTOR
  • mTOR is responsible for many things, but perhaps most important is its regulation of autophagy
  • By suppressing mTOR through things like fasting, we increase autophagy
  • Human data suggests that an intermittent dosing of rapamycin is most beneficial

It’s now known there are two mTOR complexes

A

https://podcastnotes.org/2018/08/14/mtor/

NMN

David takes 1 g of NMN and 0.5g of resveratrol every morning mixed in with some yogurt 

A new study published in Nature Metabolism finally reveals the answer to how NMN enters the cell in order to become NAD+ and that it does not need to convert into NR to do so.

Nicotinamide mononucleotide (NMN) is a biosynthetic precursor of nicotinamide adenine dinucleotide (NAD+) known to promote cellular NAD+ production and counteract age-associated pathologies associated with a decline in tissue NAD+ levels. How NMN is taken up into cells has not been entirely clear. Here we show that the Slc12a8 gene encodes a specific NMN transporter. We find that Slc12a8 is highly expressed and regulated by NAD+ in the mouse small intestine. Slc12a8 knockdown abrogates the uptake of NMN in vitro and in vivo. We further show that Slc12a8 specifically transports NMN, but not nicotinamide riboside, and that NMN transport depends on the presence of sodium ion. Slc12a8 deficiency significantly decreases NAD+ levels in the jejunum and ileum, which is associated with reduced NMN uptake as traced by doubly labelled isotopic NMN. Finally, we observe that Slc12a8 expression is upregulated in the aged mouse ileum, which contributes to the maintenance of ileal NAD+ levels. Our work identifies a specific NMN transporter and demonstrates that Slc12a8 has a critical role in regulating intestinal NAD+ metabolism.

https://www.leafscience.org/nmn-crosses-cell-membrane/

NMN and Resveratrol Explained

  • Sirtuins are genes found to control aging in yeast cells
    • There are 7 of them in humans (5 in yeast)
    • They protect all organisms from deterioration and disease
    • Sirtuins essentially “sense when we’re hungry/exercising, and send out the troops to defend us”
    • When you put more sirtuins into a yeast cell or a mouse, it lives 5-20% longer
  • NMN and Resveratrol are molecules which essentially mimic the effects of the sirtuin genes
    • “You can think of resveratrol as the accelerator pedal for the sirtuin genes, and NMN as the fuel”
      • “Resveratrol steps on the accelerator pedal of the sirtuin enzymes”
    • So you need the fuel (NMN) for resveratrol to work
  • You can buy NMN on Amazon
  • Sirtuins need NAD to work
    • “In fact, if you didn’t have NAD in your body you’d be dead in about 30 seconds”
    • As we get older, our NAD levels drop  – by the time you’re 50, your NAD levels are about half what they were when you were 20
    • NMN also boosts NAD levels (like NR)
  • Why not just take NAD?
    • It’s taken up really poorly into cells (it’s a large molecule) – Dr. Peter Attia talked about this in these Podcast Notes
    • NMN is much smaller, and thus gets into cells easier

https://www.leafscience.org/nad-transporter-identified/

https://www.leafscience.org/nmn-crosses-cell-membrane/

https://www.nature.com/articles/s42255-018-0009-4

David Sinclair, director of Harvard’s Center for the Biology of Aging

“[In my lab] we’ve been working on the molecule NAD. We published in Cell in March that by raising NAD levels we could rapidly reverse many aspects of aging in mice. [We gave] old mice the ability to run like young mice again and actually out-compete young mice. That was happening because there was improved blood flow throughout the animal. The molecule that we used is called NMN. We put that in the water supply, and after just a week we saw an increase in endurance. We’re excited about this breakthrough because it shows that we understand why we lose blood flow as we get older, and why we get tired and feel frail. But it also shows that we have a very quick way of reversing that. You could imagine people who are tired, wheelchair-bound, or even bedridden, having energy to get out and exercise again.”